cis-2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride represented below in Formula I, also known as Tramadol hydrochloride under the international non-proprietary name, is considered as a non-addicting analgesic and is useful for the management of moderate or severe pain in human patients.

The synthesis for tramadol was first disclosed in British patent Nr. 997399, which involves the Grignard reaction of 2-[(dimethylamino)methyl]cyclohexanone with 3-methoxyphenylmagnesium bromide. This reaction yields an isomeric mixture of cis & trans 2-[(dimethylamino) methyl]-1-(3-methoxyphenyl)cyclohexanol. Out of these, the cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol is the required isomer and its hydrochloride is marketed as tramadol hydrochloride. In the patent synthesis, the isomers were separated by forming a hydrochloride salt of both isomers and selectively isolating the cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride by crystallizations from 1,4-dioxane.
One disadvantage of this process is that the solvent used for the separation of isomers is 1,4-dioxane which is now considered as an unacceptable toxic material whose tolerability limits are set to an extremely low level. Another disadvantage is that repeated crystallizations were required to get a pharmaceutically acceptable isomeric purity from 1,4-dioxane as a crystallizing solvent. Furthermore 1,4-Dioxane is known to possess industrial safety hazards, as it is susceptible to form hazardous peroxides. Its exposure to workers through skin contact or inhalation poses substantial health risks, as it is a possible carcinogen.
Considerable research has been done in the past to obtain the desired cis-isomer selectively during the Grignard reaction of 2-[(dimethylamino)-methyl]-cyclohexanone with 3-methoxyphenylmagnesium bromide, but, to our knowledge, exclusive cis-isomer formation is unsuccessful. One report, U.S. Pat. No. 7,030,276, claims to get better selectivity of the desired isomer by carrying out the Grignard reaction in the presence of lithium salt, but still the trans-isomer content was reported to be 8%, which is again separated by crystallization from dioxane/water. A further report, W02003029186, describes the use of transition metal complexes of 2-[(dimethylamino)-methyl]-cyclohexanone during the Grignard reaction for enhanced isomer selectivity. The process results in transition metal salts of the (±)-cis/trans tramadol isomeric mixture with a cis/trans ratio of about 85:15 to 98:2, which were protonated with an acid to break the transition metal salts for releasing the cis-tramadol base. The acid protonation is described to facilitate the purification/isolation of cis-tramadol base from the reaction solution comprising the (±)-cis/trans tramadol transition metal salts. It is taught that the protonation procedure will not alter/improve the cis/trans isomer ratio, since the pH is kept sufficiently high to prevent the protonation of the amino group. This current application discloses various organic acid salts of tramadol for pharmaceutical application.
There are several other reports attempting to solve the problem of isolation of pure cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol from a cis/trans isomeric mixture, since the Grignard reaction invariably yields an isomeric mixture.
One such report, EP Patent No. 0940385, describes separation of cis isomer from the cis/trans mixture by crystallizing cis-tramadol base as a solid from a combination of water & water-miscible organic solvents.
Further reports, WO 99/61405 & WO 99/36390, describe the separation of isomers by forming a hydrochloride, hydrobromide or hydroiodide salt and crystallizing these salts from solvents such as nitriles and alcohols. Repetition of these processes suggests that it is hard to achieve the desired purity of cis-isomer without repeated crystallization and substantial yield losses. The reported results may be achievable on laboratory scale but the process as described would create processing problems if attempted on large scale.
Another report, European Patent No. 831082, describes isomeric separation of a cis/trans mixture by treating the mixture with electrophilic reagents such as thionyl chloride and acetic anhydride, thereby selectively reacting with the hydroxyl group of (1R,2S/1S,2R)-tramadol to give the corresponding derivatives without substantially affecting the cis-isomer and recovering the cis-isomer.
Another modification was published in EP 0778262 that describes isomeric separation of a cis/trans mixture by treating the mixture in acidic conditions using sulphuric acid or para-toluene sulphonic acid, thereby selectively dehydrating the unwanted trans-isomer to the corresponding alkene compound and the cis-isomer is isolated. Also, when the reaction was conducted under aqueous conditions, it was observed that about 50% of the trans-isomer converted to the cis-isomer, thereby achieving a higher cis-isomeric ratio. But the unwanted isomer still remains as a contaminant in the product, which is further purified by forming a hydrochloride salt and crystallizing from a solvent such as isopropyl alcohol.
A similar process was also reported in Indian Patent No.182116, which does not describe any dehydration of the trans-isomer, but conversion of unwanted trans-isomer to cis-isomer by treating with organic/inorganic acid in aqueous system. Both of the above processes operate at high temperatures for said conversion.
Yet another modification, W002066414, describes isomeric separation by forming a salt with saccharin and selectively isolating the cis-2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol as the saccharinate salt and finally converting the salt to tramadol hydrochloride.
Yet another way of recovering the cis-isomer of tramadol from an isomeric mixture is disclosed in WO03078380, which comprises crystallizing the cis-tramadol base as such from the isomeric mixture in the presence of water. This report also describes the isolation of tramadol monohydrate free base by treating the cisitrans isomeric mixture in water and adjusting the pH to 7.5 to 8.5 with an organic acid, and is claimed to improve the trans-isomer content. The process appeared to be not practical for large scale operation since the tramadol base itself is known to exist in an oily form and practically is difficult to crystallize selectively on a large scale.
Another report, U.S. Pat. No. 5,723,668, describes separation of (−)-tramadol and (+)-tramadol using L-(+)-tartaric acid, and isolation of L-(+)-tartrate salt of (−)-2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol, and finally converts it into tramadol. This process leads to four diastereomeric tartrate salts instead of satisfactory separation of the cis/trans isomers, and therefore the corresponding yield is low. To the best of our knowledge there is no report teaching the use of any organic acid for the isomeric separation of tramadol by forming an organic salt except Saccharin and L-(+)-tartaric acid which are expensive chiral separating agents, and which separate both (−) and (+) tramadol. Yet another research in this line is reported in US20030092773 by conventional racemic resolution techniques using chiral tartaric acid derivatives such as O,O-ditoluoyl tartaric acid to resolve the isomers, but these processes also suffer from the problems discussed above and, additionally, the use of chiral organic acids are not economically viable.
Therefore the object of this invention is to develop processes for the recovery of cis-2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol in higher yield without having stringent operation conditions and ensuring better isomeric separation on large scale production.